The transition from the fed to the fasting state is accompanied by several important metabolic changes. Glucose is the preferred energy source of the brain, red blood cells, and the renal medulla. Muscle and liver stores of glycogen are rapidly depleted and this leaves the fasting individual with two sources of body fuel: protein (primarily from skeletal muscle), and fatty acids (which are deposited in adipose tissue). Despite large triglyceride energy stores, fatty acids cannot be converted into glucose; although the glycerol moiety of triglycerides can be converted into glucose, this supply is quite limited. The only remaining sources of glucose are the gluconeogenic amino acids derived from the breakdown of protein.
Protein is essential to the organism and consists of either functional or structural cellular elements. Protein-containing tissue is referred to as the body cell mass (BCM), and it is this tissue that is active and functional and thus maintains the organism (Moore, F., The Metabolic Care of the Surgical Patient, W. B. Saunders Co., Philadelphia, Pa. (1959)). The utilization of protein for endogenous fuel results in a gradual erosion of the BCM, which eventually results in dysfunction. Unfortunately, the energy derived from the oxidation of endogenous fat stores is not sufficient to maintain the BCM. In his classic study of fasting subjects on a life raft in the 1940s, Gamble demonstrated that by providing 100 grams of glucose to the fasting subjects, he could decrease protein loss by 50% (Gamble, J. L., Harvey Lectures 42: 247 (1946-1947)). Based on his work, 5% dextrose has become the universal intravenous fluid used in the hospital. Two or three liters of this solution provide 100-150 g dextrose (50 g/L) which reduces net nitrogen breakdown and excretion by one-half.
A variety of studies have been performed in an attempt to further decrease the nitrogen loss in patients who cannot or do not eat. First, it should be noted that Gamble added 40 g protein to the 100 g of carbohydrate and did not observe improvement in nitrogen retention. Others have administered varying amounts of glucose and/or amino acids in a similar attempt to reduce protein loss. The most comprehensive data comes from Moore's Laboratory (Wolff, B. M., et al., Ann. Surg. 186: 518 (1977)) and is shown below.
TABLE 1 ______________________________________ Total Total Nitrogen Nitrogen Calories carbohydrates intake balance Diet kcal/day calories, kcal/day g/m.sup.2 /day g/m.sup.2 /day ______________________________________ Starvation 0 0 0 -6.44 Low-dose 568 568 0 -4.14 glucose High-dose 2278 2278 0 -3.06 glucose Amino acids 378 0 6.8 -3.22 Amino acids 888 540 7.4 -0.68 + low-dose glucose ______________________________________
As noted from the above table, the administration of calories alone has an effect of reducing negative nitrogen balance. The same is true with the administration of nitrogen; when the two nutrient sources are given together, there is an additive effect which greatly reduces the net negative nitrogen balance.
Glutamine is a nonessential amino acid that is the most abundant amino acid in whole blood and accounts for 60% of the total amino acid pool in skeletal muscle (Bergstrom, J., et al., J. Appl. Physiol. 36: 693-696 (1974)). Glutamine has a central role in several metabolic pathways. It contains two nitrogen groups which are readily transferred among tissues, provide a substrate for ammoniagenesis in the kidney, and enhance its role as a precursor for nucleotide synthesis (Marliss, E. B., et al., J. Clin. Invest. 50: 814-817 (1971); Pitts, R. F., Am. J. Med. 36: 720-742 (1962); Levintow, L., et al., J. Biol. Chem. 227: 929-941 (1957)). In addition, glutamine is actively consumed by dividing cells such as lymphocytes and intestinal epithelial cells. During catabolic states, glutamine plasma concentrations may be markedly decreased, intracellular stores may be decreased by 50% while whole plasma levels fall 20-30% (Askanazi, J., et al., Ann. Surg. 192: 78 (1980)). This depletion persists long after recovery from the catabolic process (Askanazi, J., et al., Ann. Surg. 191: 465 (1980)). Glutamine concentrations in skeletal muscle have been found to correlate well with the rate of protein synthesis (MacLennan, P. A., et al., FEBS Lett. 215: 187-191 (1987)) and its administration has been found to inhibit muscle protein breakdown in rats and dogs (MacLennan, P. A., et al., FEBS Lett. 237: 133-136 (1988)). This protein loss is not prevented by administering standard total parenteral nutrition (TPN) which is devoid of glutamine (Vinnars, E., et al., JPEN 4: 184-187 (1980)). Studies utilizing muscle biopsies in patients undergoing elective surgery have shown that glutamine-supplemented TPN diminished the decline of intracellular glutamine in muscle and counteracted the decrease in protein synthesis (Hammarqvist, F., et al., Ann. Surg. 209: 455-461 (1989)).